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L0301P30 - Patterns of Inheritance: Mendel's Laws
Importance of Genetics *many clinically important genetic diseases result from the mutation of a single gene *need to know inheritance patterns so that advice can be given to individuals and families **likelihood of developing a particular disorder **likelihood of them passing a disorder on to their children Family Tree or Pedigree *Construction of a pedigree is an essential component of history taking *vertical: generation *horizontal: oldest —> youngest *family tree uses a standardised system of symbols: *proband / index case / propositus **person who presented or was first diagnosed **indicated with arrow Definitions *allele **an alternative form of a gene found at the same locus on homologous chromosomes *homozygous **presence of two identical alleles at a given locus on a pair of homologous chromosomes *heterozygous **presence of different alleles at the same locus on a pair of homologous chromosomes *phenotype **physical appearance of an organism *genotype **genetic makeup, e.g. SS or Ss or ss *trait **any gene-determined characteristic Single Gene (Mendelian) Disorders *show Mendelian inheritance patterns *showed that: **traits occur as distinct alleles **irreversible blending does not occur Dominant-Recessive *recessive traits can disappear and reappear in successive generations *ratio of 3:1 if heterozygous parents are bred Autosomal Inheritance *trait that is determined by a gene on an autosome *dominant **trait is expressed in heterozygous state *recessive **trait it only expressed if homozygous Sex-linked Inheritance *trait that is determined by a gene on the sex chromosome Punnet Squares *shows the chance of offspring to have a particular trait diagrammatically 1. carrier x affected *50% Dd unaffected *50% dd affected *recurrence risk: 50% 2. carrier x carrier *25% DD unaffected *50% Dd unaffected carriers *25% dd affects *recurrence risk: 25% Mitochondrial DNA Inheritance *only inherited from the mother *100-1000s mtDNA - higher mutation rate **can get a mix between mutant and normal mtDNA in cells *leads to disease if mutant load is too high *variable effects - affected cellular respiration, deafness, optic neuropathy Mitochondrial Replacement Therapy *chromosomes removed from egg with mutated mitochondrial DNA and transferred to a normal egg *pronucleus is removed from mutated egg and transferred to a normal egg Autosomal Inheritance Autosomal Dominant Inheritance *relatively rare in populations *manifest in the heterozygous state *equal number of males and females affected *vertical transmission: no skipping generation *every affected person has at least one affected parent *e.g. achondroplasia **can be inherited from parents **can be de novo mutation **occurs before fertilisation Terminology: *traits may involve one organ or multiple organs **pleiotropy - 2+ unrelated effects *variable expressivity and penetrance - varying expression of symptoms even within a family *two allelic traits can be expressed in the heterozygous state *e.g. AB blood group: A,B are co-dominant Autosomal Recessive Inheritance Scenarios in randomly mating populations: *carrier x unaffected **100% unaffected but 50% are carriers *homozygous affected x unaffected **100% unaffected carriers *very rare - affected x affected **100% affected Scenario with high frequency of carriers: *carrier x carrier **25% unaffected **50% carriers **25% affected Pseudodominance *inheritance of a recessive trait mimics a dominant pattern **i.e. happens when autosomal recessive homozygote has offspring with 50% risk *affected x carrier **offspring: 50% unaffected **carriers: 50% affected Sex Linked Inheritance *caused by a gene on the X/Y chromosome X-linked Recessive Inheritance *gene carried on the X-chromosome *manifests in males (hemizygous for the mutant allele) *transmitted by **healthy heterozygotes female carrier to male children **affected males to carrier female children *can skip a generation if it passes for a male to his daughter (heterozygous carriers) *some X-linked disorders are not compatible with survival to reproductive age **thus not transmitted by affected males **e.g. Duchenne muscular dystrophy *e.g. haemophilia A - common severe coagulation disorder **mild bleeding or spontaneous haemorrhaging **affected most of royal families in Europe due to consanguinity X-linked Dominant Inheritance *uncommon *seen in heterozygous females as well as in hemizygous males **i.e. 50% males and 50% females affected *affected males transmits the trait to all his daughters *direct male to male transmission cannot occur *e.g. vitamin D resistant rickets X-inactivation *females have two copies of each X-linked gene so one is inactivated in every cell *occurs in early embryonic development **random inactivation **only occurs in somatic cells and all subsequent descendant cells have the same X chromosome inactivated **accounts for the limited expression of mutant X-linked genes in female carriers ***no severe path of mutation